This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We are using the rhesus macaque (RM) model of HIV infection and AIDS to develop potential vaccine strategies against HIV clade C (HIV-C), the world's most prevalent subtype. To test the efficacy of candidate vaccines, we have developed a series of hybrid viruses, termed simian-human immunodeficiency viruses (SHIVs), by combining genetic components of monkey AIDS virus (termed simian immunodeficiency virus (SIV)) with envelope genes cloned directly from recently transmitted HIV-C strains isolated from Zambian infants. SHIVs are then adapted to RM and large virus stocks are generated for mucosal challenges in the RM model. We vaccinated RM with recombinant SIV Gag-Pol particles, HIV-1 Tat and trimeric HIV-C gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a SHIV that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all control RM became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p0.001) and cross-nAb titers (p0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time. We are also analyzing the fine-specificity of the antibody responses in these animals to identify specific sites of envelope able to induce broadly cross-neutralizing antibodies across HIV strains, a key component of new HIV vaccines.